Abstract
The mechanism underlying pulmonary inflammation in thermal inhalation injury remains elusive. Cystic fibrosis, also hallmarked with pulmonary inflammation, is caused by mutations in CFTR, the expression of which is temperature-sensitive. We investigated whether CFTR is involved in heat-induced pulmonary inflammation. We applied heat-treatment in 16HBE14o- cells with CFTR knockdown or overexpression and heat-inhalation in rats in vivo. Heat-treatment caused significant reduction in CFTR and, reciprocally, increase in COX-2 at early stages both in vitro and in vivo. Activation of ERK/JNK, NF-κB and COX-2/PGE2 were detected in heat-treated cells, which were mimicked by knockdown, and reversed by overexpression of CFTR or VX-809, a reported CFTR mutation corrector. JNK/ERK inhibition reversed heat-/CFTR-knockdown-induced NF-κB activation, whereas NF-κB inhibitor showed no effect on JNK/ERK. IL-8 was augmented by heat-treatment or CFTR-knockdown, which was abolished by inhibition of NF-κB, JNK/ERK or COX-2. Moreover, in vitro or in vivo treatment with curcumin, a natural phenolic compound, significantly enhanced CFTR expression and reversed the heat-induced increases in COX-2/PGE2/IL-8, neutrophil infiltration and tissue damage in the airway. These results have revealed a CFTR-regulated MAPK/NF-κB pathway leading to COX-2/PGE2/IL-8 activation in thermal inhalation injury, and demonstrated therapeutic potential of curcumin for alleviating heat-induced pulmonary inflammation.
Highlights
Thermal inhalation injury is quite common in fire victims, especially in compartment fires, and is the leading cause of mortality in fire-related injuries[1]
Given the reported involvement of CFTR in regulating inflammatory responses in the airways, we hypothesized that thermal inhalation may induce downregulation of CFTR in bronchial epithelial cells leading to activation of mitogen-activated protein kinase (MAPK) and/or nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κ B) pathways and excessive COX-2/PGE2, and IL-8 production, contributing to exuberant airway inflammation seen in inhalation injury
Quantitative real-time RT-PCR (QRT-PCR) results showed a time-dependent significant reduction in CFTR mRNA after heat treatment, with the lowest level observed on day 1, which returned to normal level on day 5 after the treatment (Fig. 1a)
Summary
Thermal inhalation injury is quite common in fire victims, especially in compartment fires, and is the leading cause of mortality in fire-related injuries[1]. Cystic fibrosis (CF), a common autosomalrecessivedisorder caused by mutations of the gene encoding an anion channel, CFTR, is characterized by chronic airway inflammation with excessive production of inflammatory mediators, leading to exaggerated inflammatory response[13], which resembles pulmonary inflammation after thermal inhalation injury Both NF-κ B and MAPK pathways have been implicated in mediating the excessive inflammatory responses of CF airway epithelia, especially in the induction of COX-2 and PGE211,14,15. Given the reported involvement of CFTR in regulating inflammatory responses in the airways, we hypothesized that thermal inhalation may induce downregulation of CFTR in bronchial epithelial cells leading to activation of MAPK and/or NF-κ B pathways and excessive COX-2/PGE2, and IL-8 production, contributing to exuberant airway inflammation seen in inhalation injury. We undertook the present study to test this hypothesis and to explore a treatment strategy targeting the CFTR-regulated signaling pathway
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